Atherosclerosis is the primary cause of coronary artery disease and cerebrovascular disease, both diseases underlies about 50% of all deaths in westernized countries. The early lesions of atherosclerosis include sub-endothelial accumulations of lipid-engorged macrophages (foam cells), which are represented as “fatty streak” lesions. Fatty streaks are not clinically harmful, but they can be the precursors of more advanced fibrous and plaque-type lesions characterized by the accumulation of lipid-rich necrotic debris and smooth muscle cells (SMCs).
During the disease progression, the arterial wall gradually thickens and hardens to form an atherosclerotic plaque, resulting in the narrowing of the arterial lumen. When such intimal thickening of artery blood vessel further develops the narrowing of the arterial lumen and the plaques become fragile, unstable angina is accompanied. Subsequently, they abruptly rupture and cause ischemic symptoms or a blood clot, and often myocardial infarction or heart attack. However, since intimal thickening due to atherosclerosis progresses for many decades without marked subjective symptoms, the intimal thickening cannot easily be diagnosed before the appearance of ischemic symptoms.
When a stenotic lesion by intimal thickening is found, the vascular intervention by angioplasty including stent or percutaneous coronary angioplasty is generally performed to eliminate the luminal narrowing and to widen the vessel. However, such angioplasty procedure results in endothelial denudation, and subsequently, and intimal thickening of blood vessel due to hyperproliferation of vascular smooth muscle cells leads to restenosis. Accordingly, there is an urgent need to develop a method for rapid and easy non-invasive diagnosis of intimal thickening of blood vessel in the related field.
Until now, many attempts have been undertaken to identify the early diagnostic biomarkers for atherosclerosis in human-derived samples and model animals. The clinical data from a follow-up study of 3,209 participants in the Framingham Heart Study for more than 7 years revealed several valuable biomarkers [C-reactive protein, B-type natriuretic peptide (BNP), renin, urinary albumin, and homocysteine]. Serum proteomics and metabolomics experiments have also been aggressively conducted for many years to search for circulating biomarkers that show a correlation with the progression of the disease. Nonetheless, there have been no clinically applicable biomarkers, in particular, plasma-derived biomarkers owing to the problems of the inter-individual variability and inaccessibility of human tissues with vascular thickening.